PT88837B - METHOD FOR THE PREPARATION OF ACIDS AND AZETIDINYL-QUINOLON-CARBOXYLIC ACID ESTERS - Google Patents
METHOD FOR THE PREPARATION OF ACIDS AND AZETIDINYL-QUINOLON-CARBOXYLIC ACID ESTERS Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Description
presente invento diz respeito a um processo para a preparação de composições antibacteria nas contendo esteres e ácidos carboxilicos de azetidinilquinolona e aos métodos para utilização destes compostos.the present invention relates to a process for the preparation of antibacterial compositions containing azetidinylquinolone esters and carboxylic acids and methods for using these compounds.
A Patente dos EUA, 4.563.459, ref£ res-se a ácidos carboxilicos de 1-ciclopropil-1,4-di-hidro-4-oxo-quinolina, em que a fracção na posição 6, é hidroge nio, fluor, cloro, bromo ou nitro e a fracção na posição 7 3 4 3 4 é hidrogénio, cloro fluor, ou NR R em que R e R represen tam grupos separados ou, juntamente com o átomo de azoto em que estão posicionados, podem formar um anel heterocíclico de 5membros ou 6 membros.U.S. Patent 4,563,459 refers to 1-cyclopropyl-1,4-dihydro-4-oxo-quinoline carboxylic acids, wherein the fraction at position 6 is hydrogen, fluorine, chlorine, bromine or nitro and the fraction at position 7 3 4 3 4 is hydrogen, chlorine fluorine, or NR R in which R and R represent separate groups or, together with the nitrogen atom in which they are positioned, they can form a ring heterocyclic group of 5 members or 6 members.
A KoKai Japonesa SHO 60-89480 refere-sea compostos de formulaJapanese KoKai SHO 60-89480 refers to compounds of formula
em que Z é azoto ou CH, X ê halogenio;where Z is nitrogen or CH, X is halogen;
??
R e R são hidrogénio, acilo ou alquilo inferior;R and R are hydrogen, acyl or lower alkyl;
m é 1 ou 2; e n ê 1, 2 Nou 3. No entanto não se faz qualquerm is 1 or 2; en ê 1, 2 N or 3. However, no
revelação de compostos específicos de quinolina.development of specific quinoline compounds.
presente invento é/diz respeito a compostos de formulathe present invention is / concerns compounds of formula
COOR1 em que R1 é hidrogénio, alquilo de 1 a 6 átomos de carbo4 5 4 5 no, ou NR R em que R e R são independentemente seleccionados a partir de hidrogénio e alquilo de 1 a 6 átomos de carbono ou um catião farmaceuticamente aceitavel, ?COOR 1 where R 1 is hydrogen, alkyl of 1 to 6 carbon atoms 4 5 4 5 no, or NR R where R and R are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms or a pharmaceutically cation acceptable,?
R é hidrogénio, hidroxi, alcanoilamino de 1 a 6 átomos de carbono, morfolino, halogenio, hidroxi-alquilo de 1 a 6 fi £ átomos de carbono, COOR em que R é alquilo de 1 a 6 átomos de carbono ou um catião farmaceuticamente aceitavel, o 7 o alcoxi de 1 a 6 átomos de arbono, NR R em que R e R são independentemente seleccionados de alquilo de 1 a 6 átomos de carbono, alcanoilo de 1 a 6 átomos de carbono, hidrogeniio alcoxi de 1 a 6 átomos de carbono, amino-alquilo de 2 a 6 átomos de carbono, alquilaminoalquilo em que cada grupo alqilo é independentemente seleccionado tendo dos grupos alquilo tendo de 2 a 6 átomos de carbono e dialquilaminoalquilo em; que cada grupo alquilo é independentemente seleccionado dos grupos alquilo tendo um a 6 átomos de carbonoR is hydrogen, hydroxy, alkanoylamino of 1 to 6 carbon atoms, morpholino, halogen, hydroxy-alkyl of 1 to 6 carbon atoms, COOR where R is alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable cation , 7 o alkoxy of 1 to 6 carbon atoms, NR R where R and R are independently selected from alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, hydrogen alkoxy of 1 to 6 atoms of carbon, aminoalkyl of 2 to 6 carbon atoms, alkylaminoalkyl in which each alkyl group is independently selected having alkyl groups having from 2 to 6 carbon atoms and dialkylaminoalkyl in; that each alkyl group is independently selected from alkyl groups having one to 6 carbon atoms
8 com a condição de apenas'um dos R e R poder ser__alcoxi ;8 with the proviso that only one of the R and R can be alkoxy;
eand
R é hidrogénio, alquilo de 1 a 6 átomos de carbono, fenilo ou fenilo substituido, em que o grupo fenilo pode ser substituido por um ou dois substituintes seleccionados do grupo formado por alquilo de 1 a 6 átomos de carbono, nitro, amino, halogénio, (por ex., fluoro, cloro, bromo ou iodo), haloalquilo de 1 a 2 átomos de carbono e até 5 átomos de halogénio (por ex., fluoro, cloro, bromo ou iodo) hidroxilo ou alcoxi de 1 a 6 átomos e seus sais de adição de ácidos farmaceuticamente aceitáveis.R is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or substituted phenyl, where the phenyl group can be substituted by one or two substituents selected from the group formed by alkyl of 1 to 6 carbon atoms, nitro, amino, halogen , (eg, fluoro, chloro, bromo or iodo), haloalkyl of 1 to 2 carbon atoms and up to 5 halogen atoms (eg, fluoro, chloro, bromo or iodo) hydroxyl or alkoxy of 1 to 6 atoms and their pharmaceutically acceptable acid addition salts.
Os compostos têm actividade antibacteriana .The compounds have antibacterial activity.
presente invento também diz respeito a composições farmacêuticas contendo um veiculo ou diluente farmaceutiacmente aceitavel e um composto da formula I ou um seu sal farmaceuticamente aceitavel numa qantidade antibacterianamente eficaz. 0 presente invento também apresenta um método para tratamento de um animal, incluindo um ser humano, tendo uma doença bacteriana que consiste em se administrar ao animal (por ex., mamíferos, aves, ou peixes) uma quantidade antibaterianamente eficaz de um composto de formula I ou um seu sal de adição de acido farmaceuticamente aceitavel. 0 presente invento pode também se referir a métodos para a preparação de compostos da formula I.the present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier or diluent and a compound of formula I or a pharmaceutically acceptable salt thereof in an antibacterially effective amount. The present invention also features a method for treating an animal, including a human being, having a bacterial disease which consists of administering to the animal (e.g., mammals, birds, or fish) an antibacterially effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. The present invention can also refer to methods for the preparation of compounds of formula I.
Os compostos do invento incluem misturas racemicas e isomeros opticos. Os compostos pref£ ridos do invento são os da formula I, em que R é hidrogeniic um catião farmaceuticamente aceitavel (por ex., sodio ou potássio), ou amino.The compounds of the invention include racemic mixtures and optical isomers. Preferred compounds of the invention are those of formula I, wherein R is hydrogenated, a pharmaceutically acceptable cation (e.g., sodium or potassium), or amino.
-1 Outros compostos preferiods são os o da formula I, em que R é hidrogénio, amino, hidroxi, hidro £ ximetilo, acetilamino ou COOR6 em que R é hidrogénio;-1 Other preferred compounds are those of formula I, where R is hydrogen, amino, hydroxy, hydroxymethyl, acetylamino or COOR6 where R is hydrogen;
um catião farmaceuticamente aceitavel, ou amino., Outros •3 compostos preferidos são os da formula I, em que R é hidro genio ou fenilo.a pharmaceutically acceptable cation, or amino., Other • 3 preferred compounds are those of formula I, in which R is hydrogen or phenyl.
Os compostos mais preferidos são aqueles em que R é hidrogénio, um catião farmaceuticamente o aceitavel ou amino; R é hidrogénio, amino, ou hidroxi 3 e R ê hidrogénio ou fenilo. Os compostos preferidos especificos são os seguintes:The most preferred compounds are those in which R is hydrogen, a pharmaceutically acceptable cation or amino; R is hydrogen, amino, or hydroxy 3 and R is hydrogen or phenyl. Specific preferred compounds are as follows:
Ácidos 1-ciclopropil-6-fluoro-1,4-di-hidro-7-/“11-azetidini17 -4-oxo-3-quinolino-carboxi1ico;1-cyclopropyl-6-fluoro-1,4-dihydro-7 - / “1 1 -azetidini17 -4-oxo-3-quinoline-carboxylic acids;
Acido 1-ciclopropi1-6--fluoro-1,4-di-hidro-7-/“3 *-hidroxi-1 '-azetidinil7-4-oxo-3-quino1ino-carboxi1ico1-cyclopropi1-6 - fluoro-1,4-dihydro-7 - / “3 * -hydroxy-1 '-azetidinyl7-4-oxo-3-quino1ino-carboxylic acid
Acido 1-cicloprop i1-6-fluoro-1,4-di-hidro-7-/“3'-amino1' -azetidini17-4-0X03-quinolino-carboxi1ico.1-Cycloprop i1-6-fluoro-1,4-dihydro-7 - / “3'-amino1 '-azetidini17-4-0X03-quinoline-carboxylic acid.
Acido 1-ciclopropil-6-fluoro-1,4-di-hidro-7-/“3'-aceti1 -amino-11-azetidini17-4-oxo-3-quinolino-carboxi1ico.1-cyclopropyl-6-fluoro-1,4-dihydro-7 - / '3'-amino-1 aceti1 -azetidini17-4 1-oxo-3-quinolinecarboxylic carboxi1ico.
As composições farmacêuticas do presente invento contêm, de preferencia, os compostos e_s pecificos;preferidos acima mencionados.The pharmaceutical compositions of the present invention preferably contain the above-specified, preferred compounds.
Outros compostos do presente invento são os seguintes:Other compounds of the present invention are as follows:
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/21-fenil-31 -amino-11-azetidini1Z-4-oxo-3-quinolino-carboxi1ico;1-cyclopropi1-6-fluoro-1,4-dihydro-7- / 2 1 -phenyl-3 1 -amino-1 1 -azetidin1Z-4-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropil-6-fluoro-1,4-di-hidro-7-/-2,-metil-3lhidroxi-11-azetidini17-4-oxo-3-quinolino-carboxilico;1-cyclopropyl-6-fluoro-1,4-dihydro-7 / - 2, l-methyl-3 - hydroxy-1 -azetidini17-4 1-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-difiidro-7-/“21-meti 1-31 amino-11-azetidini17-4-οχο-3-quinolino-carboxilico;1-cyclopropi1-6-fluoro-1,4-difhydro-7 - / “2 1 -methyl 1-3 1 amino-1 1 -azetidini17-4-οχο-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/~3'-carboxil-1 1 -azetidini17-4-oxo-3-quinolino-carboxi1ico;1-cyclopropi1-6-fluoro-1,4-dihydro-7- / ~ 3'-carboxyl-1 1 -azetidini17-4-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/3'-ciano-1'azetidinil7-4-oxo-3-quinolino-carboxi1ico;1-cyclopropyl1-6-fluoro-1,4-dihydro-7- / 3'-cyano-1'azetidinyl7-4-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/“21-etil-3'hidroxi-1'-azetidini17-4-oxo-3-quinolino-carboxi1ico;1-cyclopropi1-6-fluoro-1,4-dihydro-7 - / “2 1 -ethyl-3'hydroxy-1'-azetidini17-4-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/21-propi1-31 amino-1'-azetidini17-4-oxo-3-quinolino-carboxi1ico;1-cyclopropi1-6-fluoro-1,4-dihydro-7- / 2 1 -propi1-3 1 amino-1'-azetidini17-4-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/“31-hidroximeti 1-11 - azetidini17-4-oxo-3-quinolino-carboxi1ico;1-cyclopropi1-6-fluoro-1,4-dihydro-7 - / “3 1 -hydroxymethyl 1-1 1 - azetidini17-4-oxo-3-quinoline-carboxylic acid;
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/31-amino-meti 1-11-azetidini17-4-oxo-3-quinolinocarboxi1ico;.1-cyclopropi1-6-fluoro-1,4-dihydro-7- / 3 1 -amino-methyl 1-1 1 -azetidini17-4-oxo-3-quinolinecarboxylic acid ;.
Os compostos do presente invento podem ser preparados fazendo-se reagir a quinolona de formulaThe compounds of the present invention can be prepared by reacting the quinolone of formula
em que R é como definido anteriormente e X ê fluoro, cloro, bromo, ou iodo (de preferencia fluoro, ou cloro; mais preferivelmente fluoro) com uma maina de formulawherein R is as defined above and X is fluoro, chloro, bromo, or iodo (preferably fluoro, or chloro; more preferably fluoro) with a formula formula.
IIIIII
3 em que R e R são como definidos anteriormente, um solvente inerte ou num solvente básico. Sao exemplos de solventes adequados tetra-hidrofurano, piridina, etanol, cloroformio, dimetilsulfoxido, dimetilformamida , água e suas misturas.3 wherein R and R are as defined above, an inert solvent or a basic solvent. Examples of suitable solvents are tetrahydrofuran, pyridine, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, water and mixtures thereof.
Se o solvente não ê um solvente básico tal como, px>r exemplo,If the solvent is not a basic solvent such as, for example,
10piridina, ê desejável adicionar-se uma base â mistura de rea£ ção. A base serve para facilitar a conclusão da reacção fazendo-se reagir com o fluoreto de hidrogénio que ê produzido na reacção. Prefere-se a adição de DBU (que ê uma base forte) â mistura da reacção um solvente preferido é uma mistura de acetonitrilo e 1,8-diazabiciclo (5 ,4,0 )-undec-7-eno (DBU). Especialmente preferido é o solvente de acetonitrilo contendo 1 a 3 equivalentes de DBU. A temperatura e a pressão não sao criticas. No entanto e em geral, prefere-se uma temperatura de 30 a 100°C e uma pressão de 0,5 a 2 atmosferas. Maispreferivelmente a pressão e a pressão ambiente (geralmnete cerca de 1 atmiosfera. Embora se possa formar uma quantidade significativa de produto em cerca de 5 minutos, deixa-se normalmente a reacção continuar durante a noite. 0 produto é isolado por métodos convencionais.10 pyridine, it is desirable to add a base to the reaction mixture. The base serves to facilitate the completion of the reaction by reacting with the hydrogen fluoride that is produced in the reaction. The addition of DBU (which is a strong base) to the reaction mixture is preferred. A preferred solvent is a mixture of acetonitrile and 1,8-diazabicyclo (5, 4.0) -undec-7-ene (DBU). Especially preferred is the acetonitrile solvent containing 1 to 3 equivalents of DBU. Temperature and pressure are not critical. However, in general, a temperature of 30 to 100 ° C and a pressure of 0.5 to 2 atmospheres is preferred. Most preferably, ambient pressure and pressure (generally about 1 atmosphere. Although a significant amount of product can form in about 5 minutes, the reaction is usually allowed to continue overnight. The product is isolated by conventional methods.
Por exemplo o produto pode ser isolado adicíonando-se água à mistura da reacção, ajustando-se o pH para 7,0-7,4, recolhanedo-se o precipitado resultante por filtração e a seguir lavando-se com água e secando-se o precipitado.For example, the product can be isolated by adding water to the reaction mixture, adjusting the pH to 7.0-7.4, collecting the resulting precipitate by filtration and then washing with water and drying the precipitate.
Quando se utilizam métodos convencic nais, os compostos do presente invento, em que R é diferente de hidrogénio, podem ser preparados convertendo-se um compostc 1 da formula I, em que R é hidrogénio, no correspondente éster ou amido.When conventional methods are used, the compounds of the present invention, where R is different from hydrogen, can be prepared by converting a compound 1 of formula I, where R is hydrogen, to the corresponding ester or starch.
Em alternativa um composto da formula II, em que R é hidrogénio, pode ser convertido no correspondente ester ou amido por métodos convencionais e esse ester ou amido pode a seguir ser utilizado para preparar um composto de formula I, como anteriormente descrito.Alternatively, a compound of formula II, where R is hydrogen, can be converted to the corresponding ester or starch by conventional methods and that ester or starch can then be used to prepare a compound of formula I, as previously described.
Os compostos da formula II, podem ser preparadas como descrito na Patente dos Estados Unidos no.4.563.459 .The compounds of formula II, can be prepared as described in United States Patent No. 4,563,459.
As aminas ou álcoois da formula III podem ser preparados pelos métodos bem conhecidos. Veja_ -se, por exemplo T. Okutani et al., Chem. Pharm. Buli, 22 1490-1497 (1974); S. Chatterjee et al., Chem. Comm, 93 (1968); D. Nisato et al, J. Heterocyclic Chem. 22, 961 (1985) I. Hayakawa et al., Chem. Pharm. Buli, 32 , 4907-4913 (1984); A.G. Anderson et al., J. Org. Chem. 37 3953-3955 (1972); e V.R. Gaertner J.Org.Chem. 32, 2972-2976 (1967). Assim, por exemplo, as 2-fenil- e 2-fenil substituido-3-amino-azetidinas podem ser preparadas pelo método de T. Okutani et al e 3-hidrometil-1-azetidina pode ser preparada pelo método de I. Hayakawa et al.,The amines or alcohols of formula III can be prepared by well-known methods. See, for example, T. Okutani et al., Chem. Pharm. Bull, 22 1490-1497 (1974); S. Chatterjee et al., Chem. Comm, 93 (1968); D. Nisato et al, J. Heterocyclic Chem. 22, 961 (1985) I. Hayakawa et al., Chem. Pharm. Bull, 32, 4907-4913 (1984); A.G. Anderson et al., J. Org. Chem. 37 3953-3955 (1972); and V.R. Gaertner J.Org.Chem. 32, 2972-2976 (1967). Thus, for example, 2-phenyl- and 2-substituted-phenyl-3-amino-azetidines can be prepared by the method of T. Okutani et al and 3-hydromethyl-1-azetidine can be prepared by the method of I. Hayakawa et al.,
Os sais de adição de ácidos farma ceuticamente aceitáveis da formula I são preparados de uma maneira convencional, processando-se uma solução ou suspen são da base livre da formula I com aproximadamente um equivalente químico de um acido farmaceuticamente aceitavel.The pharmaceutically acceptable acid addition salts of formula I are prepared in a conventional manner by processing a solution or suspension of the free base of formula I with approximately a chemical equivalent of a pharmaceutically acceptable acid.
Utilizam-se as técnicas convencionais de concentração e recristalização no isolamento das sais. São ilustrativos de ácidos adequados, os ácidos acético, láctico, succinico, maleico, tartárico, cítrico, glucónico, ascorbico, benzoico, metanossulfonico, cinamieo fumarico, fosfonico, clorídrico, hidrobrómico, hidroidico, sulfâmico e sulfonico.Conventional concentration and recrystallization techniques are used to isolate the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, methanesulfonic, cinnamic fumaric, phosphonic, hydrochloric, hydrobromic, hydroidic, sulfamic and sulfonic.
-12Y-12Y
I,I,
Os sais cationicos farmaceuticamente aceitáveis da formula I podem ser preparados para me todos convencionais a partir dos ácidos correspondentes, por ex., por reacção com cerca de uma quantidade equimolar da base. São adequados exemplos de sais cationicos adequados os de metais alcalinos tais como sodio ou potássio, metais alcalino-terrosos tais como, magnésio ou cálcio e aminas organicas ou amonio tais como dietanolamina ou N-metilglucamina.The pharmaceutically acceptable cationic salts of formula I can be prepared for conventional methods from the corresponding acids, e.g., by reaction with about an equimolar amount of the base. Examples of suitable cationic salts are those of alkali metals such as sodium or potassium, alkaline earth metals such as magnesium or calcium and organic amines or ammonium such as diethanolamine or N-methylglucamine.
Os compostos da formula I e os seus sais de adição de ácidos farmaceuticamente aceitáveis são antibacterianos de largo espectro uteis no tratamento de infecções bacterianas, em parte no tratamento de infecções de estirpes bacterianas gram-positivas.The compounds of formula I and their pharmaceutically acceptable acid addition salts are broad-spectrum antibacterials useful in the treatment of bacterial infections, in part in the treatment of infections of gram-positive bacterial strains.
Os compostos do presente invento podem ser administrados sozinhos, embora sejam geralmente administrados em mistura com um veiculo farmacêutico seleccionado de acordo com a via pretendida de administração e na partica farmacêutica padrão. Por exemplo, eles podem ser administrados por via oral ou na for.a de comprimidos contendo tais excipientes como amido ou lactose, ou em capsulas, quer sozinhos quer em misturas com excipientes, ou na forma de elixires ou suspensões contendo agentes aromatizantes e corantes. No caso de animais (por ex,, suínos, gado, bovino, cavalos e aves domesticas), eles são de preferencia introduzidos num alimento para animais ou na água de beber numa concentração de cerca de 5 a cerca de 5000 ppm, de preferencia cerca de 25 a cerca de 500 ppm Eles podem ser injectados parenteralmente, por exemplo, por via intramuscular, intravenosa ou sub-cutânea. Para administração parenteral, eles são de preferencia utilizados na forma de solução aquosa esteril que pode conterThe compounds of the present invention can be administered alone, although they are generally administered in admixture with a pharmaceutical carrier selected according to the intended route of administration and in standard pharmaceuticals. For example, they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules, either alone or in mixtures with excipients, or in the form of elixirs or suspensions containing flavoring and coloring agents. In the case of animals (eg pigs, cattle, cattle, horses and poultry), they are preferably introduced into an animal feed or drinking water at a concentration of about 5 to about 5000 ppm, preferably about from 25 to about 500 ppm They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are preferably used in the form of a sterile aqueous solution which may contain
-13outros solutos, por exemplo, sal ou glucose bastante para tornara solução isotonica. No caso de animais, os compos0 tos podem ser administrados por via intramuscular ou subcu tânea a niveis de dosagem de cerca de 0,1 a cerca de 50 mg/kg/dia., de preferencia cerca de 0,2 a cerca de 10 mg/kg/dia, dados numa unica dose diaria ou em ate 3 doses.-13other solutes, for example, enough salt or glucose to make the solution isotonic. In the case of animals, composed 0 ments can be administered intramuscularly or subcu taneous about 0.1 dosage levels of about 50 mg / kg / day., Preferably about 0.2 to about 10 mg / kg / day, given in a single daily dose or in up to 3 doses.
invento também apresenta compo sições farmacêuticas contendo uma quantidade antibacterianamente eficaz de um composto da formula I ou um seu sal de adição de ácidos farmaceuticamente aceitáveis juntamente com um diluente ou veiculo farmaceuticamente aceitáveisThe invention also features pharmaceutical compositions containing an antibacterially effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier.
Os compostos do presente invento podem ser administrados a seres humanos para o tratamento de doenças bacterianas quer por via oral quer parenteral e podem ser administrados por via oral a niveis de dosagem de cerca de 0,1 a cerca de 500 mg/kg/dia, de preferencia de cerca de 0,5 a cerca de 50 mg/kg/dia numa so dosagem ou am até 3 doses. Para administração intramuscular ou intra de dosagem são de cerca de 0,1 a cerca de preferencia cerca de 0,5 a cerca A administração intramuscular pode ser dose ou em atê 3 doses.The compounds of the present invention can be administered to humans for the treatment of bacterial diseases either orally or parenterally and can be administered orally at dosage levels of about 0.1 to about 500 mg / kg / day, preferably from about 0.5 to about 50 mg / kg / day in a single dose or up to 3 doses. For intramuscular or intra dosage administration they are from about 0.1 to about preferably about 0.5 to about. Intramuscular administration can be dose or up to 3 doses.
venosa, os niveis de 200 mg/kg/dia, de 50 mg/kg/dia. realizada numa solevels of 200 mg / kg / day, 50 mg / kg / day. performed in one
A administração intravenosa pode ser realizada por sistema de gota-a-gota continuo. Ocorrerão necessariamente variações dependendo do peso e estado do indivíduo a ser tratado e a via de administração especi fica escolhida, como ê do conhecimento dos peritos na técnica da especialidade.Intravenous administration can be performed by a continuous drip system. Variations will necessarily occur depending on the weight and condition of the individual to be treated and the specific route of administration chosen, as is known to those skilled in the art.
A actividade antibacteriana dos compostos do invento é revelada por teste de acordo com a técnica de replica de Steer, que é um método de teste bacteriano in vitro padrão descrito por E. Steers et al., Antibio tics and chemotherapy, 9, 307 (1959).The antibacterial activity of the compounds of the invention is revealed by testing according to the Steer replication technique, which is a standard in vitro bacterial test method described by E. Steers et al., Antibiotics and chemotherapy, 9, 307 (1959 ).
Os exemplos seguintes ilustram sem limitar, invento. Todos os pontos de fusão a que se faz referência nos Exemplos não são corrigidos.The following examples illustrate without limiting the invention. All melting points referred to in the Examples are not corrected.
Exemplo 1Example 1
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/~11-azetidini1/ -4-oxo-3-quinolino-carboxi1ico1-cyclopropyl1-6-fluoro-1,4-dihydro-7- / ~ 1 1 -azetidini1 / -4-oxo-3-quinoline-carboxylic acid
Aqueceu-se a refluxo uma mistura de acido 1-ciclopropil-6,7-difluoro-1,4-dihidro-4-oxoquinolino-3-carboxi1ico (1,591 g, 6 mmol) acetonitrilo (70 ml) azetidina (390 mg, 6,8 mmol) e DBU (913 mg 6 mmol)A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1,591 g, 6 mmol) acetonitrile (70 ml) azetidine (390 mg, 6 , 8 mmol) and DBU (913 mg 6 mmol)
Depois de apenas 5 minutos de aque cimento observou-se que se estava a precipitar material crisAfter only 5 minutes of heating, it was observed that crystalline material was precipitating
-15talino.-15talino.
Após mais 5 minutos de aquecimento a solução quente foi filtrada. A mistura de reacção foi seguidamente deixada arrefecer â temperatura ambiente durante 1 hora.After a further 5 minutes of heating the hot solution was filtered. The reaction mixture was then allowed to cool to room temperature over 1 hour.
material solido precipitado foi recolhido por filtração, lavado primeiramente com acetonitrilo e a seguir com eter etílico e depois seco para dar 650 mg do composto do titulo, p.f. 298-299°C (dec).precipitated solid material was collected by filtration, washed first with acetonitrile and then with ethyl ether and then dried to give 650 mg of the title compound, mp 298-299 ° C (dec).
NMR (DMS0-D6): 1,12-1,13 d e 1,26-1,28 d, 4H, de ciclopropano; 2,3-2,4, m, 2H, de Cg azetidina; 3,2-3,7, q, 1H de ciclopropano; 4,19-4,24 q, 4H de azetidina C2 e C4i 6,82-6,85, d, 1H de Cg 7,74-7,78 , d, 1H de Cg;NMR (DMS0-D6): 1.12-1.13 of 1.26-1.28 d, 4H, cyclopropane; 2.3-2.4, m, 2H, of Cg azetidine; 3.2-3.7, q, 1H cyclopropane; 4.19-4.24 q, 4H of azetidine C 2 and C 4 i 6.82-6.85, d, 1H of Cg 7.74-7.78, d, 1H of C g ;
8,55, s , 1H, de ·8.55, s, 1H, de ·
Obteve-se uma segunda colheita de cristais, que foram lavados e secos como descrito anteri ormente para dar 210 mg do composto do titulo, m.p. 297-299°C (dec). 0 rendimento combinado foi de 48% ·A second crop of crystals was obtained, which were washed and dried as previously described to give 210 mg of the title compound, m.p. 297-299 ° C (dec). The combined yield was 48% ·
-16Exemplo 2-16Example 2
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/3'-amino-1'-azetidinil7-4-oxo-3-quinolino-carboxi1ico e seu sal de hi. drocloreto1-cyclopropi1-6-fluoro-1,4-dihydro-7- / 3'-amino-1'-azetidinyl7-4-oxo-3-quinoline-carboxylic acid and its hi salt. drochloride
Levou-se a refluxo uma mistura de 3-amino-1-azetidina (80 mg, 0,048 mmol) de acido 1ciclopropi1-6,7-difluoro-1,4-dihidro-4-oxo-quinolina-3-carbpxilico (10,6 mg, 0,04 mol) de DBU (0,0113 ml, de 12,1 mg, 0,08 mmol) em 5 ml de acetonitrilo sob azoto (79-80°C) durante 3 horas, e foi a segunda a seguir deixada em repouso à temperatura ambiente sob azoto durante a noite.A mixture of 3-amino-1-azetidine (80 mg, 0.048 mmol) of 1cyclopropyl1-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (10, 6 mg, 0.04 mol) of DBU (0.0113 ml, 12.1 mg, 0.08 mmol) in 5 ml of acetonitrile under nitrogen (79-80 ° C) for 3 hours, and was the second to then left to stand at room temperature under nitrogen overnight.
A mistura de reacção foi a seguir filtrada e o bolo húmido foi lavado com acetonitrilo e depois com éter etilico. 0 bolo foi a seguir seco in vacuo para dar 15 mg do composto do titulo p.f. 277-278°C.The reaction mixture was then filtered and the wet cake was washed with acetonitrile and then with ethyl ether. The cake was then dried in vacuo to give 15 mg of the title compound mp 277-278 ° C.
sal de hidrocloreto de composto do titulo foi preparado adicionando-se 130 mg (0,04 mmol) do composto do titulo a HC1 metanolico contendo uma quantidade equivalente (0,04 mmol) de HC1, agitando-se â temperatura ambiente durante 4 horas. Os cristais foram recolhidos por filtração, lavados com éter etilico e secos para dar 22,3 mg do sal de hdirocloreto, p.f. de acima de 300°C.hydrochloride salt of the title compound was prepared by adding 130 mg (0.04 mmol) of the title compound to methanol HCl containing an equivalent amount (0.04 mmol) of HCl, stirring at room temperature for 4 hours. The crystals were collected by filtration, washed with ethyl ether and dried to give 22.3 mg of the hdirochloride salt, m.p. from above 300 ° C.
-17NMR (DMS0-D6); 1,12-1,13 d, e 1,26-1,28 d, 4H, de ciclopropano, 3,8 s, 1H, de ciclopropano; 4,05-4,25 m, 4H de C2 * 1, e C4' azetidina; 4,46-4,52 q, 1H de azetidina C3 1; 6,92-6,98 d, 1H de Cg; 7,80-7,86 d, 1H, de C5; 8,6 s, 1H de C2; 8,68-8,84 d, 2H de NH2.-17NMR (DMS0-D6); 1.12-1.13 d, and 1.26-1.28 d, 4H, cyclopropane, 3.8 s, 1H, cyclopropane; 4.05-4.25 m, 4H of C 2 * 1 , and C4 'azetidine; 4.46-4.52 q, 1H of C3 1 azetidine; 6.92-6.98 d, 1H of Cg; 7.80-7.86 d, 1H, from C 5 ; 8.6 s, 1H of C 2 ; 8.68-8.84 d, 2H of NH 2 .
Exemplo 3Example 3
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/3 1 -hidroxi-1 1 -azetidini17-4-oxo-3-quinolino-carboxi1ico1-cyclopropi1-6-fluoro-1,4-dihydro-7- / 3 1 -hydroxy-1 1 -azetidini17-4-oxo-3-quinoline-carboxylic acid
Levou-se a refluxo sob azoto, durante 2,5 horas, uma mistura de hidrocloreto de 3-hidroxi -1-azetidina (120 mg, 1,1 mol) acido 1-ciclopropil-6,7-difluoro-1 ,4-di-hidro-4-oxo-quinolino-3-carboxi1ico (265 mg mmol), e 299 ml (2 mmol) de DBU em 10 ml de acetonitrilo e seguidamente filtrou-se a quente.A mixture of 3-hydroxy -1-azetidine hydrochloride (120 mg, 1.1 mol) 1-cyclopropyl-6,7-difluoro-1, 4- was refluxed under nitrogen for 2.5 hours dihydro-4-oxo-quinoline-3-carboxylic (265 mg mmol), and 299 ml (2 mmol) of DBU in 10 ml of acetonitrile and then hot filtered.
bolo húmido foi lavado com aceto nitrilo e seco para dar 130 mg de composto do titulo, p.f. 294-295°C (dec).wet cake was washed with nitrile acetate and dried to give 130 mg of the title compound, mp 294-295 ° C (dec).
-18Exemplo 4-18Example 4
Acido 1-ciclopropil-6-fluoro-1,4-di-hidro-7-/”3 '-carboxil-1 1-azetidini17-4-oxo-3-quinolino-carboxi1ico e seu carboxilato de 3'-sodio1-cyclopropyl-6-fluoro-1,4-dihydro-7 - / ”3 '-carboxyl-1 1 -azetidini17-4-oxo-3-quinoline-carboxylic acid and its 3'-sodium carboxylate
Levou-se a refluxo spb azoto, duranet 2 horas, uma mistura de acido 1-ciclopropi1-6,7-di fluoro-1,4-di-hidro-4-oxo-quinolino-3-carboxilico (132,5 mg, 0,005 mmol) acido azetidino-3-carboxi1ico (556mg, 0,055 mmol) e DBU (0,075 mol 0,05 mol) em 5 ml de acetonitrilo.A mixture of 1-cyclopropyl1-6,7-di-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was refluxed for 2 hours during 2 hours. 0.005 mmol) azetidine-3-carboxylic acid (556mg, 0.055 mmol) and DBU (0.075 mol 0.05 mol) in 5 ml of acetonitrile.
A mistura da reacção foi a seguir deixada arrefecer à temperatura ambiente durante 2 horas.The reaction mixture was then allowed to cool to room temperature over 2 hours.
solido resultante foi suspenso em 3 ml de agua e o pH foi ajustado para 8,5 péla adição de solução NaHCOg aquosa saturada. Adicionou-se a seguir éter etílico. A mistura resultante foi agitada num funil de separação e separou-se a camada organica. A camada aquosa foi filtrada e a solução filtrada para foi seca por congelação durante a noite, obtendo-se 180 mg (92%) do composto do titulo, na forma de sal dissodico, p.f. 287-289°C (dec).The resulting solid was suspended in 3 ml of water and the pH was adjusted to 8.5 by the addition of saturated aqueous NaHCOg solution. Ethyl ether was then added. The resulting mixture was stirred in a separatory funnel and the organic layer was separated. The aqueous layer was filtered and the filtered solution was freeze-dried overnight, obtaining 180 mg (92%) of the title compound, as disodium salt, m.p. 287-289 ° C (dec).
Exemplo 5Example 5
Acido 1-ciclopropi1-6-fluoro-1,4-di-hidro-7-/~3'-acetilami no-11-azetidinil7-4-oxo-3-quinolino-carboxilico e seu sal de hidrocloreto.1-cyclopropi1-6-fluoro-1,4-dihydro-7- / ~ 3'-acetylamino-1 1 -azetidinyl7-4-oxo-3-quinoline-carboxylic acid and its hydrochloride salt.
Levou-se a refluxo, sob azoto (79-80 C), durante uma hora uma mistura de 3-acetilamino-1-azetidina (110 mg), 0 ,963 mmol) acido 1-ciclopropi1-6 ,7 -difluoro-1,4-di-hidro-4-oxo-quinolino-3-carboxi1ico (212mg) 0,8 mmol) e DBU (0,134 ml, 137 mg, 0,9 mmol), em 10 ml de acetonitrilo, que se deixou depois em repouso à temperatura ambiente sob azoto durante a noite. A mistura de reacção foi a seguir filtrada e o bolo húmido foi lavado com acetonitrilo e depois com éter etilico. 0 tolo foi a seguir seco in vacuo, obtendo-se 311 mg do composto de titulo.A mixture of 3-acetylamino-1-azetidine (110 mg), 0.963 mmol) 1-cyclopropyl1-6,7-difluoro-1 was refluxed under nitrogen (79-80 ° C) for one hour. , 4-dihydro-4-oxo-quinoline-3-carboxylic (212mg) 0.8mmol) and DBU (0.134ml, 137mg, 0.9mmol), in 10ml of acetonitrile, which was then left in standing at room temperature under nitrogen overnight. The reaction mixture was then filtered and the wet cake was washed with acetonitrile and then with ethyl ether. The fool was then dried in vacuo, yielding 311 mg of the title compound.
Preparou-se o sal de hidrocloreto adicionando-se o composto do titulo (100 mg) a HC1 metanoU co contendo uma quantidade equivalente de HC1 e agitando-se à temperatura ambiente durante 30 minutos.The hydrochloride salt was prepared by adding the title compound (100 mg) to methanol / HCl containing an equivalent amount of HCl and stirring at room temperature for 30 minutes.
material solido que se formou foi filtrado, lavado com acetonitrilo e seco in vacuo obtendo-se 83,7 mg (76%) do sal de hidrocloreto , p.f. 265-266°C dec.solid material that formed was filtered, washed with acetonitrile and dried in vacuo to obtain 83.7 mg (76%) of the hydrochloride salt, mp 265-266 ° C dec.
Ac ido 1-ciclopropi1-6-fluoro-1.4-di-hidro-7-/2'-metil-31 hidroxi-1 1 -azetidini17-4-oxo-3-quinolino-carboxi1ico1-cyclopropi1-6-fluoro-1,4-dihydro-7- / 2'-methyl-3 1 hydroxy-1 1 -azetidini17-4-oxo-3-quinoline-carboxylic acid
Seguindo-se o método do Exemplo 1. mas utilizando-se 2-metil-3-hidroxi-1-azetidina no lugar da azetidina. obteve-se o composto do titulo, p.f. acima de 300°’ C.Following the method of Example 1. but using 2-methyl-3-hydroxy-1-azetidine in place of azetidine. the title compound was obtained, m.p. over 300 ° C.
Exemplo 7Example 7
Acido 1-ciclopropi1-6-fluoro-1.4-dihidro-7-/“3 1-hidroxi-meti1-11-azetidini17-4-oxo-3-quinolino-carboxi1icoAcid 1-ciclopropi1-6-fluoro-1,4-dihydro-7 - / "3-hydroxy-1 meti1-1 -azetidini17-4 1-oxo-3-quinolinecarboxylic carboxi1ico
Levou-se a refluxo sob azoto, durante 3 horas, uma mistura de 3-hidroxi-meti1-1-azetidina (4,4 mg, 0,05 mmol), acido 1-ciclopropi1-6,7-difluoro-1 ,4di-hidro-4-oxo-quinolino-3-carboxilico (10,6 mg, 0,04iftol) e DBU (0,0113 ml, 12,1 mg 0,08 mmol) em 5 ml de acetonitri_ lo, que foi deixada em repouso à temperatura ambiente sob azoto durante a noite. A mistura de reacção foi a seguir filtrada e o bolo húmido foi lavado com acetonitrilo e secoA mixture of 3-hydroxymethyl1-1-azetidine (4.4 mg, 0.05 mmol), 1-cyclopropyl1-6,7-difluoro-1, 4di was refluxed under nitrogen for 3 hours -hydro-4-oxo-quinoline-3-carboxylic (10.6 mg, 0.04iftol) and DBU (0.0113 ml, 12.1 mg 0.08 mmol) in 5 ml of acetonitrile, which was left in standing at room temperature under nitrogen overnight. The reaction mixture was then filtered and the wet cake was washed with acetonitrile and dried
-21in vacuo, obtendo-se 9,9 mg (59%) do composto do titulo p.f. cerca de 300°C.-21in vacuo, yielding 9.9 mg (59%) of the title compound m.p. about 300 ° C.
Exemplo 8Example 8
Acido 1 -dclopropi1-6-fluoro-1,4-di-hidro-7-/“2‘-fenil-3lamino-1'-azetidinilZ-4-oxo-3-quinolino-carboxi1ico1-dclopropi1-6-fluoro-1,4-dihydro-7 - / “2'-phenyl-3 l amino-1'-azetidinylZ-4-oxo-3-quinoline-carboxylic acid
Levou-se a refluxo durante 8 hora di-hidrocloreto de 2-feni1-3-amino-1-azetidina (9,24 mg), 0,05 mmol), ácido 1-ciclopropi1-6,7-difluoro-1,4-di-hidro-4-oxo-quinolino-3-carboxilico (10,6 mg, 0,04 mmol) e DBU (12,1 mg, 0,08 mmol) em 15 ml de acetonitrilo, que foi depois deixada em repouso à temperatura ambiente durante a noite, sob azoto. A mistura foi a seguir filtrada, lavada com acetonitrilo, e seca in vacuo, obtendo-se 6,3 mg (40%), p.f. acima de 300°C.Reflux was carried out for 8 hours 2-pheni1-3-amino-1-azetidine dihydrochloride (9.24 mg), 0.05 mmol), 1-cyclopropi1-6,7-difluoro-1,4 -dihydro-4-oxo-quinoline-3-carboxylic (10.6 mg, 0.04 mmol) and DBU (12.1 mg, 0.08 mmol) in 15 ml of acetonitrile, which was then left to stand at room temperature overnight, under nitrogen. The mixture was then filtered, washed with acetonitrile, and dried in vacuo, yielding 6.3 mg (40%), m.p. above 300 ° C.
Exemplo 9Example 9
Os compostos dos titulos dos Exem pios 1, 2, 3 e 5 foram submetidos a teste quanto à actividade antibacteriana in vitro, utilizando-se a técnica de replica de Steer.The title compounds of Examples 1, 2, 3 and 5 were tested for antibacterial activity in vitro, using the Steer replication technique.
Verificou-se que os c ompostos eram activos contra Staphilococcus aureus, Staphylococcus epidermis, Streptococcus pyrogenes, Escherichia coli , Klebsiella pneumoniae, Klebsiella oxytoca, Pasteurella multocida, Serratia marcescens, Neisseria sicca, Enterobacter aerogenes, Enterobacter cloacae, e Morganella morganii a niveis inferiores a 3,2 microgramas por ml.The compounds were found to be active against Staphilococcus aureus, Staphylococcus epidermis, Streptococcus pyrogenes, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pasteurella multocida, Serratia marcescens, Neisseria sicca, Enterobactere aerogenes, 3.2 micrograms per ml.
Claims (8)
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PCT/US1987/002792 WO1989003828A1 (en) | 1987-10-26 | 1987-10-26 | Azetidinyl quinolone carboxylic acids and esters |
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NO (1) | NO892616L (en) |
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FR2634483B2 (en) * | 1987-12-29 | 1994-03-04 | Esteve Labor Dr | DERIVATIVES OF ACIDS 7- (1-AZETIDINYL) -1,4-DIHYDRO-4-OXOQUINOLEINE-3-CARBOXYLIQUES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
US5173484A (en) * | 1988-02-05 | 1992-12-22 | Bayer Aktiengesellschaft | Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them |
EP0366189A3 (en) * | 1988-10-24 | 1992-01-02 | Norwich Eaton Pharmaceuticals, Inc. | Novel antimicrobial lactam-quinolones |
FR2644455B1 (en) * | 1989-03-16 | 1994-09-23 | Esteve Labor Dr | SUBSTITUTED PYRIDONE CARBOXYLIC ACID AZETIDINYL ACID DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
FR2654728B2 (en) * | 1989-03-16 | 1994-09-23 | Esteve Labor Dr | SUBSTITUTED PYRIDONE CARBOXYLIC ACID DERIVATIVES OF AZETIDINYL, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS. |
FR2649106A2 (en) * | 1989-06-29 | 1991-01-04 | Esteve Labor Dr | Derivatives of azetidinyl-substituted pyridonecarboxylic acids, their preparation and their application as medicaments |
NO177302C (en) * | 1989-03-16 | 1995-08-23 | Esteve Labor Dr | Analogous Process for Preparing Therapeutically Active Substituted Azetidinyl Quinolone (Naphthyridone) Carboxylic Acid Derivatives |
FR2690161B1 (en) * | 1992-04-16 | 1995-06-30 | Esteve Labor Dr | SUBSTITUTED PYRIDONE AZETIDINYL DERIVATIVES WITH ANTIMICROBIAL ACTIVITY. |
US5885983A (en) * | 1996-05-10 | 1999-03-23 | Bristol-Myers Squibb Company | Inhibitors of microsomal triglyceride transfer protein and method |
WO2005019224A2 (en) * | 2003-06-06 | 2005-03-03 | Cadila Healthcare Limited | Novel antiinfective compounds |
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US4670444B1 (en) * | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
NZ208470A (en) * | 1983-07-18 | 1988-06-30 | Abbott Lab | 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives and antibacterial compositions containing such |
JPS6089480A (en) * | 1983-10-21 | 1985-05-20 | Dainippon Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative |
JPS60126284A (en) * | 1983-12-09 | 1985-07-05 | Dainippon Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative and salt thereof |
US4623650A (en) * | 1984-12-06 | 1986-11-18 | Pfizer Inc. | Antibiotic derivatives of 7-phenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
JPS61137885A (en) * | 1984-12-08 | 1986-06-25 | Dainippon Pharmaceut Co Ltd | 1,8-naphthylidine derivative, its ester and salt |
JPS61152682A (en) * | 1984-12-27 | 1986-07-11 | Dainippon Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative, its ester and salt |
JPS61282382A (en) * | 1985-06-06 | 1986-12-12 | Dainippon Pharmaceut Co Ltd | Phenyl substituted 1,8-naphthyridine derivative, ester and salt thereof |
JPS62469A (en) * | 1985-06-27 | 1987-01-06 | Dainippon Pharmaceut Co Ltd | Novel quinolone derivative and ester and salt thereof |
JPS6219883A (en) * | 1985-07-19 | 1987-01-28 | Ricoh Co Ltd | Color-changeable developing device |
JPH0674260B2 (en) * | 1985-08-01 | 1994-09-21 | 大日本製薬株式会社 | Quinoline derivatives, their esters and their salts |
JPS62215572A (en) * | 1986-03-17 | 1987-09-22 | Kyorin Pharmaceut Co Ltd | Quinolone carboxylic acid derivative |
NO871333L (en) * | 1986-03-31 | 1987-10-01 | Sankyo Co | KINOLIN-3 CARBOXYLIC ACID DERIVATIVES, PROCEDURES FOR PREPARING AND USING THEREOF. |
JPH0689480A (en) * | 1992-09-09 | 1994-03-29 | Ricoh Co Ltd | Magneto-optical recording and reproducing device |
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1987
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1988
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1989
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- 1989-06-23 NO NO89892616A patent/NO892616L/en unknown
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Publication number | Publication date |
---|---|
IE883217L (en) | 1989-04-26 |
KR900006741B1 (en) | 1990-09-20 |
ES2061680T3 (en) | 1994-12-16 |
FI893048A0 (en) | 1989-06-21 |
IL88086A0 (en) | 1989-06-30 |
EP0314362A2 (en) | 1989-05-03 |
ATE100805T1 (en) | 1994-02-15 |
DE3887443D1 (en) | 1994-03-10 |
ZA887927B (en) | 1990-06-27 |
AU2432588A (en) | 1988-10-25 |
DK591588A (en) | 1989-04-27 |
MY103436A (en) | 1993-06-30 |
DK591588D0 (en) | 1988-10-25 |
IE63284B1 (en) | 1995-04-05 |
JPH01146879A (en) | 1989-06-08 |
HUT52497A (en) | 1990-07-28 |
EP0314362B1 (en) | 1994-01-26 |
US5039683A (en) | 1991-08-13 |
FI893048A (en) | 1989-06-21 |
NZ226689A (en) | 1990-03-27 |
AU602431B2 (en) | 1990-10-11 |
IL88086A (en) | 1997-01-10 |
HU205105B (en) | 1992-03-30 |
EP0314362A3 (en) | 1989-10-18 |
NO892616D0 (en) | 1989-06-23 |
WO1989003828A1 (en) | 1989-05-05 |
KR890006616A (en) | 1989-06-14 |
NO892616L (en) | 1989-06-23 |
DE3887443T2 (en) | 1994-05-11 |
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